INTRODUCTION: Amyloid precursor protein (APP) undergoes striking changes following traumatic brain injury (TBI). Considering its role in the control of gene expression, we investigated whether APP regulates transcription and translation following TBI. METHODS: We assessed brain morphology (n = 4-9 mice/group), transcriptome (n = 3 mice/group), proteome (n = 3 mice/group), and behavior (n = 17-27 mice/group) of wild-type (WT) and APP knock-out (KO) mice either untreated or 10-weeks following TBI. RESULTS: After TBI, WT mice displayed transcriptional programs consistent with late stages of brain repair, hub genes were predicted to impact translation and brain proteome showed subtle changes. APP KO mice largely replicated this transcriptional repertoire, but showed no transcriptional nor translational response to TBI. DISCUSSION: The similarities between WT mice following TBI and APP KO mice suggest that developmental APP deficiency induces a condition reminiscent of late stages of brain repair, hampering the control of gene expression in response to injury. HIGHLIGHTS: 10-weeks after TBI, brains exhibit transcriptional profiles consistent with late stage of brain repair. Developmental APP deficiency maintains brains perpetually in an immature state akin to late stages of brain repair. APP responds to TBI by changes in gene expression at a transcriptional and translational level. APP deficiency precludes molecular brain changes in response to TBI.

Central European Institute of Technology at Masaryk University Brno Czech Republic

Department of Anesthesiology University of California San Diego San Diego California USA

Department of Neurology Barrow Neurological Institute Phoenix Arizona USA

Department of Neurology Royal Gloucester Hospital Gloucestershire Hospitals NHS Foundation Trust Gloucester UK

Institute for Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czech Republic

Neuropathology and Ocular Pathology Department Oxford University Hospitals NHS Foundation Trust Oxford UK

PsychoGenics Inc 215 College Road Paramus New Jersey New Jersey USA

Translational Aging and Neuroscience Program Center for Translational Medicine International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Veterans Affairs San Diego Healthcare System San Diego California USA

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